Polymeric materials have been used for many years for producing medical devices such as sutures, surgical clips, catheters, vascular grafts, and implants. Such materials have also been used for the controlled release of biologically active agents with the discovery over 30 years ago that silicone elastomers could control the rate of release of lipophilic dyes (J. Folkman et al., J. Surg. Res. 4:139-142 (1964)). This led to the evaluation of silicone elastomers for the controlled release of pharmaceutical compounds. A number of these products have been commercialized, including the Norplant.RTM. subdermal implants for controlled release of levonorgestrel (J. Osti, Sci. Technol. Pract. Pharm. 34:309-312 (1987); see also, U.S. Pat. Nos. 4,341,728 (Robertson) and 4,292,965 (Nash, The Population Council, Inc.), and Compudose.RTM. implants (Eli Lilly and Company) for delivery of estradiol to promote growth in steers (Hsieh et al., Drug Develop. & Ind. Pharm. 13:2651-2666 (1987)). Other nonbiodegradable polymers such as polyethylene, poly(hydroxyethyl methacrylate) and ethylene-vinyl acetate copolymers have also been used for drug delivery.
More recently, biodegradable polymers have been used in drug delivery devices because of their biodegradability. These polymers include those based upon lactide, glycolide, .epsilon.-caprolactone and copolymers thereof (Yolles, U.S. Pat. No. 3,887,699; Kent, U.S. Pat. No. 4,675,189; Pitt, U.S. Pat. No. 4,148,871; Schindler, U.S. Pat. No. 4,702,917). Polyorthoesters and polyanhydrides have also been used as bioerodible matrices for drug release and as medical devices (U.S. Pat. Nos. 4,093,709 and 4,138,344, Choi and Heller; U.S. Pat. No. 4,906,474, Domb and Langer, M.I.T.).
The above-described polymers are solids at room temperature and, as a result, are shaped into solid structures outside the body and then inserted into the body by surgical procedures. If prepared as microparticles, microspheres, microcapsules or nanoparticles, such forms can be injected into the body using standard syringes and needles.
U.S. Pat. No. 4,938,763 (Dunn) describes methods and compositions in which biodegradable polymers are combined with biocompatible solvents to form a composition that can be administered into the body, whereupon the solvent diffuses or leaches away from the polymer composition into body fluids. Because the polymers are insoluble in water, they coagulate or precipitate upon contact with aqueous body fluid to form a solid implant for use as a medical device. If a drug is included in the polymer composition, it becomes incorporated into the implant matrix as the polymer coagulates.
A disadvantage of such a system is that a high concentration of organic solvent may be needed to fully dissolve the polymer. Polymeric compositions can also have a high flow viscosity because of the resistance of the long polymer chains to movement. In addition, the time period of biodegradation of some polymers can only by reduced to a certain minimum because of the need to hydrolyze the polymer chains to short chain lengths before the polymer becomes solubilized or metabolized. Therefore, there is a need for materials that are biodegradable, and will dissolve in biocompatible solvents to form a relatively non-viscous composition, and precipitate or coagulate to form a solid implant upon exposure to water.
Non-polymeric materials have been described for use as solid drug delivery matrices. Examples include cholesterol in the form of pellets for dispensing steroids (Shimkin et al., Endocrinology 29:1020 (1941)), naltrexone (Misra, "Narcotic antagonists: Naltrexone pharmochemistry and sustained release preparations," Research Monograph 28, Willette et al., eds., National Institute on Drug Abuse (1981), and a luteinizing hormone-releasing system (Kent, U.S. Pat. No. 4,452,775). Phospholipids are another non-polymeric material that have been used for preparing liposomes for drug delivery.
A disadvantage of those systems is that solid cholesterol pellets require a surgical incision or a large trochar for implantation. Although, the liposomes formed from phospholipids and from cholesterol can be injected using standard syringes and needles, these materials require considerable preparation, have low stability, and only a small amount of drug can be encapsulated within the small particles and released with time. In addition, because liposomes are small particles, they are poorly retained at the implantation site. Also, the small liposome particles are difficult to remove if complications arise and it is necessary to terminate treatment.
Accordingly, an object of the invention is to provide a composition made of nonpolymeric material that can be used to provide a solid implant in-situ. Another object is to provide a solid implant that will provide a shorter biodegradation time than an implant formed from a biodegradable polymer. Yet another object is to provide a composition having a low flow viscosity that can be administered by a pressure applicator, and will form a solid biodegradable implant in-situ in a body for use as a medical device and/or a controlled delivery system for a drug.